The 100 most-cited articles in Alzheimer s & Dementia, 2016

This report describes the public health impact of Alzheimer's disease, including incidence and prevalence, mortality rates, costs of care, and the overall impact on caregivers and society. It also examines in detail the financial impact of Alzheimer's on families, including annual costs to families and the difficult decisions families must often make to pay those costs. An estimated 5.4 million Americans have Alzheimer's disease. By mid-century, the number of people living with Alzheimer's disease in the United States is projected to grow to 13.8 million, fueled in large part by the aging baby boom generation. Today, someone in the country develops Alzheimer's disease every 66 seconds. By 2050, one new case of Alzheimer's is expected to develop every 33 seconds, resulting in nearly 1 million new cases per year. In 2013, official death certificates recorded 84,767 deaths from Alzheimer's disease, making it the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age ≥ 65 years. Between 2000 and 2013, deaths resulting from stroke, heart…

During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

Several attempts have been made to treat Alzheimer's disease (AD) using anti-amyloid strategies with disappointing results. It is clear that the "amyloid cascade hypothesis" alone cannot fully explain the neuronal damage in AD, as evidenced both by autopsy and imaging studies. Neuroinflammation plays a significant role in neurodegenerative diseases, whereas the debate is ongoing about its precise role, whether it is protective or harmful. In this review, we focus on the potential mechanism of glial activation and how local and systemic factors influence disease progression. We focus on neuroinflammation in AD, especially in the earliest stages, a vicious cycle of glial priming, release of pro-inflammatory factors, and neuronal damage. We review the evidence from imaging studies, regarding the temporal relationship between amyloid deposition and neuroinflammation, the influence of systemic inflammation on glial activation, both in acute and chronic stimulation and the relevance of inflammation as a diagnostic and therapeutic target.

INTRODUCTION: In 2010, Alzheimer's Disease International presented estimates of the global cost of illness (COI) of dementia. Since then, new studies have been conducted, and the number of people with dementia has increased. Here, we present an update of the global cost estimates. METHODS: This is a societal, prevalence-based global COI study. RESULTS: The worldwide costs of dementia were estimated at United States (US) $818 billion in 2015, an increase of 35% since 2010; 86% of the costs occur in high-income countries. Costs of informal care and the direct costs of social care still contribute similar proportions of total costs, whereas the costs in the medical sector are much lower. The threshold of US $1 trillion will be crossed by 2018. DISCUSSION: Worldwide costs of dementia are enormous and still inequitably distributed. The increase in costs arises from increases in numbers of people with dementia and in increases in per person costs.

INTRODUCTION: Our goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro-deoxyglucose (FDG) PET, and MRI cortical thickness. METHODS: We examined five methods for determining cut points. RESULTS: The reliable worsening method produced a cut point only for amyloid PET. The specificity, sensitivity, and accuracy of cognitively impaired versus young clinically normal (CN) methods labeled the most people abnormal and all gave similar cut points for tau PET, FDG PET, and cortical thickness. Cut points defined using the accuracy of cognitively impaired versus age-matched CN method labeled fewer people abnormal. DISCUSSION: In the future, we will use a single cut point for amyloid PET (standardized uptake value ratio, 1.42; centiloid, 19) based on the reliable worsening cut point method. We will base lenient cut points for tau PET, FDG PET, and cortical thickness on the accuracy of cognitively impaired versus young CN method and base conservative cut points on the accuracy of cognitively impaired versus age-matched CN method.

INTRODUCTION: Reducing racial/ethnic disparities is a primary objective of the National Alzheimer's Plan (NAPA), yet direct comparisons within large samples representing diversity of the United States are lacking. METHODS: Dementia incidence from January 1, 2000 to December 31, 2013 and a 25-year cumulative risk in 274,283 health care members aged 64+ (n = 18,778 African-American, n = 4543 American Indian/Alaska Native [AIAN], n = 21,000 Latino, n = 440 Pacific Islander, n = 206,490 white, n = 23,032 Asian-Americans). Cox proportional hazard models were adjusted for age, sex, medical utilization, and comorbidities. RESULTS: Dementia incidence (n = 59,555) was highest for African-Americans (26.6/1000 person-years) and AIANs (22.2/1000 person-years); intermediate for Latinos (19.6/1000 person-years), Pacific Islanders (19.6/1000 person-years), and whites (19.3/1000 person-years) and lowest among Asian-Americans (15.2/1000 person-years). Risk was 65% greater for African-Americans (hazard ratio = 1.65; 95% confidence interval = 1.58-1.72) versus Asian-Americans. Cumulative 25-year risk…

Utilizing β-amyloid precursor protein (βAPP) as a substrate, α-, β-, and γ-secretases are responsible for sequential cleavage events leading to the formation of β-amyloid, the classic pathologic hallmark of Alzheimer’s Disease. Members of this class of proteases also catalyze the activation of numerous other membrane-localized proteins implicated in cell growth and neuroinflammation such as NOTCH and the Interleukin/TNF-receptor family, respectively. This investigation addresses if an in vitro Chlamydia pneumoniae infection of human astrocytes affects the processing of βAPP through modifying the protein expression of the following βAPP processing proteases: A Disintegrin and Metalloproteinase-10 (ADAM10), βAPP cleaving enzyme-1 (BACE1), and presenilin-1 (PSEN1). Human astrocytoma cells (CCF-STTG1) were infected in vitro with Chlamydia pneumoniae strain AR39 (MOI=1). At 6-72 hours post infection, protein level of β-amyloid, ADAM10, BACE1, and presenilin-1 N-terminal fragment (NTF) relative to uninfected controls were detected by immunofluorescence and quantified by western blot…

As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (APOE) risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries.

INTRODUCTION: Subjective cognitive decline (SCD) manifesting before clinical impairment could serve as a target population for early intervention trials in Alzheimer's disease (AD). A working group, the Subjective Cognitive Decline Initiative (SCD-I), published SCD research criteria in the context of preclinical AD. To successfully apply them, a number of issues regarding assessment and implementation of SCD needed to be addressed. METHODS: Members of the SCD-I met to identify and agree on topics relevant to SCD criteria operationalization in research settings. Initial ideas and recommendations were discussed with other SCD-I working group members and modified accordingly. RESULTS: Topics included SCD inclusion and exclusion criteria, together with the informant's role in defining SCD presence and the impact of demographic factors. DISCUSSION: Recommendations for the operationalization of SCD in differing research settings, with the aim of harmonization of SCD measurement across studies are proposed, to enhance comparability and generalizability across studies.

INTRODUCTION: The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI-3, which began on August 1, 2016, is a 5-year renewal of the current ADNI-2 study. METHODS: ADNI-3 will follow current and additional subjects with normal cognition, mild cognitive impairment, and AD using innovative technologies such as tau imaging, magnetic resonance imaging sequences for connectivity analyses, and a highly automated immunoassay platform and mass spectroscopy approach for cerebrospinal fluid biomarker analysis. A Systems Biology/pathway approach will be used to identify genetic factors for subject selection/enrichment. Amyloid positron emission tomography scanning will be standardized using the Centiloid method. The Brain Health Registry will help recruit subjects and monitor subject cognition. RESULTS: Multimodal analyses will provide insight into AD pathophysiology and disease progression. DISCUSSION: ADNI-3 will aim to inform AD treatment trials and facilitate development of AD disease-modifying…

INTRODUCTION: As the relationship between delirium and long-term cognitive decline has not been well-explored, we evaluated this association in a prospective study. METHODS: SAGES is an ongoing study involving 560 adults age 70 years or more without dementia scheduled for major surgery. Delirium was assessed daily in the postoperative period using the Confusion Assessment Method. General Cognitive Performance (GCP) and the Informant Questionnaire for Cognitive Decline in the Elderly were assessed preoperatively then repeatedly out to 36 months. RESULTS: On average, patients with postoperative delirium had significantly lower preoperative cognitive performance, greater immediate (1 month) impairment, equivalent recovery at 2 months, and significantly greater long-term cognitive decline relative to the nondelirium group. Proxy reports corroborated the clinical significance of the long-term cognitive decline in delirious patients. DISCUSSION: Cognitive decline after surgery is biphasic and accelerated among persons with delirium. The pace of long-term decline is similar to that seen…

OBJECTIVE: To identify incidence and prevalence of dementia in racial and ethnic populations in the United States. METHODS: A systematic review of literature. RESULTS: A total of 1215 studies were reviewed; 114 were included. Dementia prevalence rates reported for age 65+ years from a low of 6.3% in Japanese Americans, 12.9% in Caribbean Hispanic Americans, 12.2% in Guamanian Chamorro and ranged widely in African Americans from 7.2% to 20.9%. Dementia annual incidence for African American (mean = 2.6%; SD = 1%; range, 1.4%-5.5%) and Caribbean Hispanic populations were significantly higher (mean, 3.6%; SD, 1.2%; range, 2.3%-5.3%) than Mexican American and Japanese Americans and non-Latino white populations (0.8%-2.7%), P < .001. CONCLUSIONS: Data are needed for American Indian, most Asian, and Pacific Islander populations. Disaggregation of large race/ethnic classifications is warranted due to within-population heterogeneity in incidence and prevalence. African American and Caribbean Hispanic studies showed higher incidence of dementia. A nationwide approach is needed to identify…

INTRODUCTION: Alzheimer's disease (AD) progression follows a specific spreading pattern, emphasizing the need to characterize those brain areas that degenerate first. The brainstem's locus coeruleus (LC) is the first area to develop neurofibrillary changes (neurofibrillary tangles [NFTs]). METHODS: The methods include unbiased stereological analyses in human brainstems to estimate LC volume and neuronal population in controls and individuals across all AD stages. RESULTS: As the Braak stage increases by 1 unit, the LC volume decreases by 8.4%. Neuronal loss started only midway through AD progression. Age-related changes spare the LC. DISCUSSION: The long gap between NFT accumulation and neuronal loss suggests that a second trigger may be necessary to induce neuronal death in AD. Imaging studies should determine whether LC volumetry can replicate the stage-wise atrophy observed here and how these changes are specific to AD. LC volumetry may develop into a screening biomarker for selecting high-yield candidates to undergo expensive and less accessible positron emission tomography…

INTRODUCTION: Rapid growth of the older adult population requires greater epidemiologic characterization of dementia. We developed national prevalence estimates of diagnosed dementia and subtypes in the highest risk United States (US) population. METHODS: We analyzed Centers for Medicare & Medicaid administrative enrollment and claims data for 100% of Medicare fee-for-service beneficiaries enrolled during 2011-2013 and age ≥68 years as of December 31, 2013 (n = 21.6 million). RESULTS: Over 3.1 million (14.4%) beneficiaries had a claim for a service and/or treatment for any dementia subtype. Dementia not otherwise specified was the most common diagnosis (present in 92.9%). The most common subtype was Alzheimer's (43.5%), followed by vascular (14.5%), Lewy body (5.4%), frontotemporal (1.0%), and alcohol induced (0.7%). The prevalence of other types of diagnosed dementia was 0.2%. DISCUSSION: This study is the first to document concurrent prevalence of primary dementia subtypes among this US population. The findings can assist in prioritizing dementia research, clinical services, and…

The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer's disease (AD). Blood-based biomarkers have significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.

INTRODUCTION: The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimer's disease in autosomal dominant Alzheimer's disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN-TU now plans to add new drugs to the platform, designated as the Next Generation (NexGen) prevention trial. METHODS: In collaboration with ADAD families, philanthropic organizations, academic leaders, the DIAN-TU Pharma Consortium, the National Institutes of Health, and regulatory colleagues, the DIAN-TU developed innovative clinical study designs for the DIAN-TU NexGen prevention trial. RESULTS: Our expanded trial toolbox consists of a disease progression model for ADAD, primary end point DIAN-TU cognitive performance composite, biomarker development, self-administered cognitive assessments, adaptive dose adjustments, and blinded data collection through the last participant completion. CONCLUSION: These steps represent elements to improve efficacy of the adaptive…

INTRODUCTION: TREM2 is a lipid-sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial. METHODS: We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes. RESULTS: We provide more evidence for increased AD risk associated with several TREM2 variants, and show that these variants decreased or markedly increased binding to TREM2 ligands. We identify HDL and LDL as novel TREM2 ligands. We also show that TREM2 expression in human monocytes is minimal compared to monocyte-derived dendritic cells. DISCUSSION: Our results suggest that TREM2 signaling helps protect against AD but can cause harm in excess, supporting the idea that proper TREM2 function is important to counteract disease progression.

INTRODUCTION: Dementia is a heterogeneous neurodegenerative disease, whose etiology results from a complex interplay between environmental and genetic factors. METHODS: We searched PubMed to identify meta-analyses of observational studies that examined associations between nongenetic factors and dementia. We estimated the summary effect size using random-effects and fixed-effects model, the 95% CI, and the 95% prediction interval. We assessed the between-study heterogeneity (I-square), evidence of small-study effects, and excess significance. RESULTS: A total of 76 unique associations were examined. By applying standardized criteria, seven associations presented convincing evidence. These associations pertained to benzodiazepines use, depression at any age, late-life depression, and frequency of social contacts for all types of dementia; late-life depression for Alzheimer's disease; and type 2 diabetes mellitus for vascular dementia and Alzheimer's disease. DISCUSSION: Several risk factors present substantial evidence for association with dementia and should be assessed as potential…

INTRODUCTION: Loss of synapses best correlates to cognitive deficits in Alzheimer's disease (AD) in which oligomeric neurotoxic species of amyloid-β appears to contribute synaptic pathology. Although a number of clinical pathologic studies have been performed with limited sample size, there are no systematic studies encompassing large samples. Therefore, we performed a meta-analysis study. METHODS: We identified 417 publications reporting postmortem synapse and synaptic marker loss from AD patients. Two meta-analyses were performed using a single database of subselected publications and calculating the standard mean differences. RESULTS: Meta-analysis confirmed synaptic loss in selected brain regions is an early event in AD pathogenesis. The second meta-analysis of 57 synaptic markers revealed that presynaptic makers were affected more than postsynaptic markers. DISCUSSION: The present meta-analysis study showed a consistent synaptic loss across brain regions and that molecular machinery including endosomal pathways, vesicular assembly mechanisms, glutamate receptors, and axonal…

Abstract Introduction Small vessel disease (SVD) is a common contributor to dementia. Subtle blood‐brain barrier (BBB) leakage may be important in SVD‐induced brain damage. Methods We assessed imaging, clinical variables, and cognition in patients with mild (i.e., nondisabling) ischemic lacunar or cortical stroke. We analyzed BBB leakage, interstitial fluid, and white matter integrity using multimodal tissue‐specific spatial analysis around white matter hyperintensities (WMH). We assessed predictors of 1 year cognition, recurrent stroke, and dependency. Results In 201 patients, median age 67 (range 34–97), BBB leakage, and interstitial fluid were higher in WMH than normal‐appearing white matter; leakage in normal‐appearing white matter increased with proximity to WMH (P < .0001), with WMH severity (P = .033), age (P = .03), and hypertension (P < .0001). BBB leakage in WMH predicted declining cognition at 1 year. Discussion BBB leakage increases in normal‐appearing white matter with WMH and predicts worsening cognition. Interventions to reduce BBB leakage may prevent SVD‐associated…

More than 5 million Americans are living with Alzheimer's disease (AD) today, and nearly two-thirds of Americans with AD are women. This sex difference may be due to the higher longevity women generally experience; however, increasing evidence suggests that longevity alone is not a sufficient explanation and there may be other factors at play. The Alzheimer's Association convened an expert think tank to focus on the state of the science and level of evidence around gender and biological sex differences for AD, including the knowledge gaps and areas of science that need to be more fully addressed. This article summarizes the think tank discussion, moving forward a research agenda and funding program to better understand the biological underpinnings of sex- and gender-related disparities of risk for AD.

INTRODUCTION: Numerous diagnostic criteria have tried to tackle the variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment (VCI) but none have been universally accepted. These criteria have not been readily comparable, impacting on clinical diagnosis rates and in turn prevalence estimates, research, and treatment. METHODS: The Vascular Impairment of Cognition Classification Consensus Study (VICCCS) involved participants (81% academic researchers) from 27 countries in an online Delphi consensus study. Participants reviewed previously proposed concepts to develop new guidelines. RESULTS: VICCCS had a mean of 122 (98-153) respondents across the study and a 67% threshold to represent consensus. VICCCS redefined VCI including classification of mild and major forms of VCI and subtypes. It proposes new standardized VCI-associated terminology and future research priorities to address gaps in current knowledge. DISCUSSION: VICCCS proposes a consensus-based updated conceptualization of VCI intended to facilitate standardization in research.

INTRODUCTION: The relationship of diabetes to specific neuropathologic causes of dementia is incompletely understood. METHODS: We used logistic regression to evaluate the association between diabetes and infarcts, Braak neurofibrillary tangle stage, and neuritic plaque score in 2365 autopsied persons. In a subset of >1300 persons with available cognitive data, we examined the association between diabetes and cognition using Poisson regression. RESULTS: Diabetes increased odds of brain infarcts (odds ratio [OR] = 1.57, P < .0001), specifically lacunes (OR = 1.71, P < .0001), but not Alzheimer's disease neuropathology. Diabetes plus infarcts was associated with lower cognitive scores at end of life than infarcts or diabetes alone, and diabetes plus high level of Alzheimer's neuropathologic changes was associated with lower mini-mental state examination scores than the pathology alone. DISCUSSION: This study supports the conclusions that diabetes increases the risk of cerebrovascular but not Alzheimer's disease pathology, and at least some of diabetes' relationship to cognitive…

INTRODUCTION: Apathy is common in neurocognitive disorders (NCDs) such as Alzheimer's disease and mild cognitive impairment. Although the definition of apathy is inconsistent in the literature, apathy is primarily defined as a loss of motivation and decreased interest in daily activities. METHODS: The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Syndromes Professional Interest Area (NPS-PIA) Apathy workgroup reviewed the latest research regarding apathy in NCDs. RESULTS: Progress has recently been made in three areas relevant to apathy: (1) phenomenology, including the use of diagnostic criteria and novel instruments for measurement, (2) neurobiology, including neuroimaging, neuropathological and biomarker correlates, and (3) interventions, including pharmacologic, nonpharmacologic, and noninvasive neuromodulatory approaches. DISCUSSION: Recent progress confirms that apathy has a significant impact on those with major NCD and those with mild NCDs. As such, it is an important target for research and…

Abstract Introduction The aim of this study was to (1) replicate previous associations between six blood lipids and Alzheimer's disease (AD) (Proitsi et al 2015) and (2) identify novel associations between lipids, clinical AD diagnosis, disease progression and brain atrophy (left/right hippocampus/entorhinal cortex). Methods We performed untargeted lipidomic analysis on 148 AD and 152 elderly control plasma samples and used univariate and multivariate analysis methods. Results We replicated our previous lipids associations and reported novel associations between lipids molecules and all phenotypes. A combination of 24 molecules classified AD patients with >70% accuracy in a test and a validation data set, and we identified lipid signatures that predicted disease progression (R2 = 0.10, test data set) and brain atrophy (R2 ≥ 0.14, all test data sets except left entorhinal cortex). We putatively identified a number of metabolic features including cholesteryl esters/triglycerides and phosphatidylcholines. Discussion Blood lipids are promising AD biomarkers that may lead to new…

INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood. METHODS: Tau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by single molecule array technology with 303 subjects. RESULTS: The efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls and correlated with cerebrospinal fluid tau. CONCLUSIONS: Tau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD.

INTRODUCTION: The objective of this study was to determine the utility of subjective memory decline (SMD) to predict episodic memory change and rates of clinical progression in cognitively normal older adults with evidence of high β-amyloid burden (CN Aβ+). METHODS: Fifty-eight CN Aβ+ participants from the Australian Imaging, Biomarkers, and Lifestyle study responded to an SMD questionnaire and underwent comprehensive neuropsychological assessments. Participant data for three follow-up assessments were analyzed. RESULTS: In CN Aβ+, subjects with high SMD did not exhibit significantly greater episodic memory decline than those with low SMD. High SMD was related to greater rates of progression to mild cognitive impairment or Alzheimer's disease (AD) dementia (hazard ratio = 5.1; 95% confidence interval, 1.4-20.0, P = .02) compared with low SMD. High SMD was associated with greater depressive symptomatology and smaller left hippocampal volume. DISCUSSION: High SMD is a harbinger of greater rates of clinical progression in preclinical AD. Although SMD reflects broader diagnostic…

Significant progress has been made in characterizing the biological changes occurring in preclinical Alzheimer's disease (AD). Cognitive dysfunction has been viewed, however, as a late-stage phenomenon, despite increasing evidence that changes may be detected in the decades preceding dementia. In the absence of comprehensive evidence-based guidelines for preclinical cognitive assessment, longitudinal cohort and neuroimaging studies have been reviewed to determine the temporal order and brain biomarker correlates of specific cognitive functions. Episodic memory decline was observed to be the most salient cognitive function, correlating with high levels of amyloid deposition and hypoconnectivity across large-scale brain networks. Prospective studies point to early decline in both episodic and semantic memory processing as well as executive functions in the predementia period. The cognitive tests have, however, been principally those used to diagnose dementia. New procedures are required which target more finely the medial temporal lobe subregions first affected by clinically silent AD…

INTRODUCTION: Whether co-occurring neuropathologies interact or independently affect clinical disease progression is uncertain. We estimated rates of clinical progression and tested whether associations between clinical progression and Alzheimer's disease neuropathology (ADNP) were modified by co-occurring Lewy body disease (LBD) or vascular brain injury (VBI). METHODS: Linear mixed effects models evaluated longitudinal trends in the Clinical Dementia Rating Scale Sum of Boxes on 2046 autopsied participants seen at a U.S. Alzheimer's Disease Center. RESULTS: Annual clinical progression was slightly faster for ADNP + LBD compared with ADNP only (P = .06) and slightly slower for ADNP + VBI (P = .003). Differences in progression were less than expected if each neuropathology independently contributed to progression; ADNP interacted with LBD (P = .002) and VBI (P = .003). In secondary models, the effect of additional pathologies on clinical progression was greater in those with intermediate compared with high levels of ADNP. DISCUSSION: The impact of co-occurring pathologies on…

Abstract Introduction Aggregation of tau is a hallmark of many neurodegenerative diseases, and tau imaging with positron emission tomography (PET) may allow early diagnosis and treatment monitoring. We assessed binding of the PET tracer [18F]AV‐1451 in a range of dementias. Methods Phosphorimaging was used to quantify binding to postmortem brain tissue from 33 patients with different, histopathologically characterized, neurodegenerative dementias. Results [18F]AV‐1451 showed high specific binding in cases with Alzheimer's disease (AD), moderate binding in Pick's disease and frontotemporal dementia with parkinsonism‐17, and low but displaceable binding in corticobasal degeneration, progressive supranuclear palsy, non–tau proteinopathies, and in controls without pathology. Tracer binding did not correlate with tau load within disease groups. Discussion [18F]AV‐1451 binds to tau in AD, and some other tauopathies. However, evidence for a non–tau binding site and lack of correlation between tracer binding and antibody staining suggest that reliable quantification of tau load with this…

INTRODUCTION: Subjective cognitive decline (SCD) could indicate preclinical Alzheimer's disease, but the existing literature is confounded by heterogeneous approaches to studying SCD. We assessed the differential cognitive, affective, and neuroimaging correlates of two aspects of SCD: reporting high cognitive difficulties on a self-rated questionnaire versus consulting at a memory clinic. METHODS: We compared 28 patients from a memory clinic with isolated SCD, 35 community-recruited elders with similarly high levels of self-reported cognitive difficulties, and 35 community-recruited controls with low self-reported cognitive difficulties. RESULTS: Increased anxiety and amyloid β deposition were observed in both groups with high self-reported difficulties, whereas subclinical depression and (hippocampal) atrophy were specifically associated with medical help seeking. Cognitive tests showed no group differences. DISCUSSION: These results further validate the concept of SCD in both community- and clinic-based groups. Yet, recruitment methods influence associated biomarkers and affective…

Late-life depression is frequently associated with cognitive impairment. Depressive symptoms are often associated with or even precede a dementia syndrome. Moreover, depressive disorders increase the risk of persistence for mild cognitive impairment and dementia. Here, we present both the current state of evidence and future perspectives regarding the integration and value of clinical assessments, neuropsychological, neurochemical, and neuroimaging biomarkers for the etiological classification of the dementia versus the depression syndrome and for the prognosis of depression relating to dementia risk. Finally, we summarize the existing evidence for both pharmacotherapy and psychotherapy of depression in demented patients. There is an urgent need for large-scale collaborative research to elucidate the role and interplay of clinical and biological features in elderly individuals with depressive disorders who are at elevated risk for developing dementia. To overcome barriers for successful drug development, we propose the introduction of the precision medicine paradigm to this research…

INTRODUCTION: Our objective was to compare the levels of three synaptic proteins involved in different steps of the synaptic transmission: Rab3A, SNAP25, and neurogranin, in three common forms of dementia: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia. METHODS: A total of 129 postmortem human brain samples were analyzed in brain regional specific manner exploring their associations with morphologic changes and cognitive decline. RESULTS: We have observed robust changes reflecting synaptic dysfunction in all studied dementia groups. There were significant associations between the rate of cognitive decline and decreased levels of Rab3 in DLB in the inferior parietal lobe and SNAP25 in AD in the prefrontal cortex. Of particular note, synaptic proteins significantly discriminated between dementia cases and controls with over 90% sensitivity and specificity. DISCUSSION: Our findings suggest that the proposition that synaptic markers can predict cognitive decline in AD, should be extended to Lewy body diseases.

INTRODUCTION: We performed a comprehensive quantitative proteomics study on human hippocampus tissue involving all Braak stages to assess changes in protein abundance over the various stages of Alzheimer's disease (AD). METHODS: Hippocampal subareas CA1 and subiculum of 40 cases were isolated using laser capture microdissection and analyzed using mass spectrometry. Immunoblotting and immunohistochemistry were used for validation. RESULTS: Over the Braak stages, an altered expression was found for 372 proteins including changes in levels of extracellular matrix components, and in calcium-dependent signaling proteins. Early changes were observed in levels of proteins related to cytoskeletal dynamics and synaptic components including an increase in RIMS1 and GRIK4. Several synaptic proteins, such as BSN, LIN7A, DLG2, -3, and -4, exhibit an early-up, late-down expression pattern. DISCUSSION: This study provides new insight into AD-dependent changes in protein levels in the hippocampus during AD pathology, identifying potential novel therapeutic targets and biomarkers.

INTRODUCTION: Recently, quantitative metabolomics identified a panel of 10 plasma lipids that were highly predictive of conversion to Alzheimer's disease (AD) in cognitively normal older individuals (n = 28, area under the curve [AUC] = 0.92, sensitivity/specificity of 90%/90%). METHODS: Quantitative targeted metabolomics in serum using an identical method as in the index study. RESULTS: We failed to replicate these findings in a substantially larger study from two independent cohorts-the Baltimore Longitudinal Study of Aging ([BLSA], n = 93, AUC = 0.642, sensitivity/specificity of 51.6%/65.7%) and the Age, Gene/Environment Susceptibility-Reykjavik Study ([AGES-RS], n = 100, AUC = 0.395, sensitivity/specificity of 47.0%/36.0%). In analyses applying machine learning methods to all 187 metabolite concentrations assayed, we find a modest signal in the BLSA with distinct metabolites associated with the preclinical and symptomatic stages of AD, whereas the same methods gave poor classification accuracies in the AGES-RS samples. DISCUSSION: We believe that ours is the largest blood…

INTRODUCTION: We examined the association between decreased cerebral blood flow (CBF) and cognitive impairment in Alzheimer's disease (AD), mild cognitive impairment (MCI), and subjective cognitive decline (SCD). METHODS: We included 161 AD, 95 MCI, and 143 SCD patients from the Amsterdam Dementia Cohort. We used 3-T pseudo-continuous arterial spin labeling to estimate whole-brain and regional partial volume-corrected CBF. Neuropsychological tests covered global cognition and five cognitive domains. Associations were investigated using linear regression analyses. RESULTS: In the whole sample, reduced overall and regional CBF was associated with impairment in all cognitive domains. We found significant interactions between diagnosis and CBF for language and between diagnosis and parietal CBF for global cognition and executive functioning. Stratification showed that decreased CBF was associated with worse performance in AD patients but not in MCI or SCD. DISCUSSION: Our results suggest that CBF may have potential as a functional marker of disease severity.

INTRODUCTION: The Mediterranean diet (MeDi) is associated with reduced risk of cognitive impairment, but it is unclear whether it is associated with better brain imaging biomarkers. METHODS: Among 672 cognitively normal participants (mean age, 79.8 years, 52.5% men), we investigated associations of MeDi score and MeDi components with magnetic resonance imaging measures of cortical thickness for the four lobes separately and averaged (average lobar). RESULTS: Higher MeDi score was associated with larger frontal, parietal, occipital, and average lobar cortical thickness. Higher legume and fish intakes were associated with larger cortical thickness: legumes with larger superior parietal, inferior parietal, precuneus, parietal, occipital, lingual, and fish with larger precuneus, superior parietal, posterior cingulate, parietal, and inferior parietal. Higher carbohydrate and sugar intakes were associated with lower entorhinal cortical thickness. DISCUSSION: In this sample of elderly persons, higher adherence to MeDi was associated with larger cortical thickness. These cross-sectional…

INTRODUCTION: Tau protein levels in plasma may be a marker of neuronal damage. We examined associations between plasma tau levels and Alzheimer's disease (AD)-related magnetic resonance imaging (MRI) and positron emission tomography (PET) neuroimaging measures among nondemented individuals. METHODS: Participants included 378 cognitively normal (CN) and 161 mild cognitive impairment (MCI) individuals enrolled in the Mayo Clinic Study of Aging with concurrent neuropsychological measures and amyloid PET, fluorodeoxyglucose PET, and MRI. Baseline plasma tau levels were measured using the Quanterix Simoa-HD1 tau assay. RESULTS: Plasma tau levels were higher in MCI compared with CN (4.34 vs. 4.14 pg/mL, P = .078). In regression models adjusted for age, gender, education, and APOE, higher plasma tau was associated with worse memory performance (b = -0.30, P = .02) and abnormal cortical thickness in an AD signature region (odds ratio = 1.80, P = .018). DISCUSSION: Plasma tau is associated with cortical thickness and memory performance. Longitudinal studies will better elucidate the…

INTRODUCTION: Circadian alterations are prevalent in Alzheimer's disease (AD) and may contribute to cognitive impairment, behavioral symptoms, and neurodegeneration. Epigenetic mechanisms regulate the circadian clock, and changes in DNA methylation have been reported in AD brains, but the pathways that mediate circadian deregulation in AD are incompletely understood. We hypothesized that aberrant DNA methylation may affect circadian rhythms in AD. METHODS: We investigated DNA methylation, transcription, and expression of BMAL1, a positive regulator of the circadian clock, in cultured fibroblasts and brain samples from two independent cohorts of aging and AD. RESULTS: DNA methylation modulated rhythmic expression of clock genes in cultured fibroblasts. Moreover, rhythmic methylation of BMAL1 was altered in AD brains and fibroblasts and correlated with transcription cycles. DISCUSSION: Our results indicate that cycles of DNA methylation contribute to the regulation of BMAL1 rhythms in the brain. Hence, aberrant epigenetic patterns may be linked to circadian alterations in AD.

Abstract This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid‐β1–42, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost‐effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add‐on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker…

Alzheimer's Association Research Roundtable Fall 2015-Tau: From research to clinical development. Tau pathology is recognized as the key driver of disease progression in Alzheimer's and other neurodegenerative diseases. Although this makes tau an attractive target for the development of novel diagnostic and therapeutic strategies, the mechanisms underlying the onset and progression of tau-related neurotoxicity remain elusive. Recent strides in the development of sophisticated preclinical models and the emergence of tau PET imaging and fluid biomarkers provide new opportunities to increase our understanding of tau biology, overcome translational challenges, and accelerate the advancement of tau therapeutics from bench to bedside. With this in mind, the Alzheimer's Association convened a Research Roundtable in October 2015, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of tau pathogenic pathways and review the evolution of tau therapeutics and biomarkers currently in development. The meeting provided a forum to share…

Abstract This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid‐β1–42, tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia. The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost‐effectiveness, and (iv) interpretation of results. The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided.

INTRODUCTION: We have comprehensively described the expression profiles of mitochondrial DNA and nuclear DNA genes that encode subunits of the respiratory oxidative phosphorylation (OXPHOS) complexes (I-V) in the hippocampus from young controls, age matched, mild cognitively impaired (MCI), and Alzheimer's disease (AD) subjects. METHODS: Hippocampal tissues from 44 non-AD controls (NC), 10 amnestic MCI, and 18 AD cases were analyzed on Affymetrix Hg-U133 plus 2.0 arrays. RESULTS: The microarray data revealed significant down regulation in OXPHOS genes in AD, particularly those encoded in the nucleus. In contrast, there was up regulation of the same gene(s) in MCI subjects compared to AD and ND cases. No significant differences were observed in mtDNA genes identified in the array between AD, ND, and MCI subjects except one mt-ND6. DISCUSSION: Our findings suggest that restoration of the expression of nuclear-encoded OXPHOS genes in aging could be a viable strategy for blunting AD progression.

INTRODUCTION: Individuals with Down syndrome (DS) exhibit Alzheimer's disease (AD) neuropathology and dementia early in life. Blood biomarkers of AD neuropathology would be valuable, as non-AD intellectual disabilities of DS and AD dementia overlap clinically. We hypothesized that elevations of amyloid β (Aβ) peptides and phosphorylated-tau in neuronal exosomes may document preclinical AD. METHODS: , P-T181-tau, and P-S396-tau were quantified by enzyme-linked immunosorbent assays in extracts of neuronal exosomes purified from blood of individuals with DS and age-matched controls. RESULTS: , P-T181-tau, and P-S396-tau were significantly elevated in individuals with DS compared with age-matched controls at all ages beginning in childhood. No significant gender differences were observed. DISCUSSION: , P-T181-tau, and P-S396-tau in individuals with DS may provide a basis for early intervention as targeted treatments become available.

INTRODUCTION: Neurofibrillary pathology of abnormally hyperphosphorylated tau (P-tau) is a hallmark of Alzheimer's disease (AD) and other tauopathies. Tau pathology can be experimentally induced and propagated. However, what induces the prion-like transmission character to tau and produces morphologically distinct tau lesions remains elusive. METHODS: We investigated the role of hyperphosphorylation in the spread of tau pathology in hTau transgenic mice. RESULTS: We found that intrahippocampal injection with AD P-tau, but not nonphosphorylated tau, produced numerous P-tau tangles and neuropil threads locally and in neocortex lateral to injection and upstream to the hippocampus. Dephosphorylation of AD P-tau with protein phosphatase-2A dramatically reduced and switched tau pathology from neurofibrillary tangles to argyrophilic grain-like morphology. CONCLUSIONS: Our findings show that abnormal hyperphosphorylation of tau determines the spread and morphology of tau lesions and that the propagation of tau pathology takes place both locally and in axonally connected areas and highlight…

INTRODUCTION: The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain. METHODS: We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study. RESULTS: We confirm that variation in/near APOE/TOMM40 (P = 6 × 10(-14)) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10(-4)), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10(-10) OR = 1.9 [1.5-2.3]); rs72907046 near FAM46A (P = 1 × 10(-9) OR = 3.2 [2.1-4.9]); and rs2525776 near SEMA3C (P = 1 × 10(-8), OR = 3.3 [2.1-5.1]). DISCUSSION: We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may…

INTRODUCTION: Many people with mild cognitive impairment (MCI) suffer from concomitant depression or anxiety. Whether MCI increases the risk of future depression or anxiety is unknown. METHODS: In the Rotterdam Study, cross-sectional (n = 4168) and longitudinal associations (n = 2967) of MCI with Diagnostic and Statistical Manual of Mental Disorders-depressive and anxiety disorders-were assessed (2002-2005 to 2009-2011). RESULTS: At baseline, 413 persons had MCI; 125 (22 MCI and 103 non-MCI) had a depressive disorder and 330 had an anxiety disorder (46 MCI and 284 non-MCI). In longitudinal depression analysis, of the 212 persons with prevalent MCI, 6 (2.8%) developed depression compared with 29 (1%) in the nonexposed group. In longitudinal anxiety analysis, 11 (7.3%) of the 151 with prevalent MCI developed anxiety, compared with 75 (3.4%) in nonexposed group. Persons with MCI had more depressive and anxiety disorders and also a higher risk of developing depressive disorder, odds ratio (OR) 3.13 (95% confidence interval [CI]: 1.26, 7.77), and anxiety disorder, OR 2.59 (95% CI: 1.31,…

INTRODUCTION: Information and communication technology (ICT) is potentially mature enough to empower outdoor and social activities in dementia. However, actual ICT-based devices have limited functionality and impact, mainly limited to safety. What is an ideal operational framework to enhance this field to support outdoor and social activities? METHODS: Review of literature and cross-disciplinary expert discussion. RESULTS: A situation-aware ICT requires a flexible fine-tuning by stakeholders of system usability and complexity of function, and of user safety and autonomy. It should operate by artificial intelligence/machine learning and should reflect harmonized stakeholder values, social context, and user residual cognitive functions. ICT services should be proposed at the prodromal stage of dementia and should be carefully validated within the life space of users in terms of quality of life, social activities, and costs. DISCUSSION: The operational framework has the potential to produce ICT and services with high clinical impact but requires substantial investment.

INTRODUCTION: TREM2 is involved in the regulation of inflammatory response and phagocytosis. A soluble fragment (sTREM2) is often found abnormally increased in cerebrospinal fluid (CSF) in Alzheimer's disease (AD). METHODS: One hundred fourteen participants (45 control, 19 preclinical, 27 mild cognitive impairment [MCI], and 23 AD) underwent CSF sTREM2 determination and magnetic resonance imaging (MRI). We studied the association between CSF sTREM2, gray matter volume, and water motion diffusivity and anisotropy across groups. RESULTS: In MCI patients, a positive correlation between CSF sTREM2 and gray matter volume was found in the bilateral inferior and middle temporal cortices, precuneus, the supramarginal, and angular gyri, after controlling by age, sex, and p-tau. A negative correlation with mean diffusivity was detected in overlapping regions, among others. DISCUSSION: In early AD, augmented CSF sTREM2 levels correspond with cerebral MRI features typical of brain swelling, supporting a role for TREM2 in the regulation of the neuroinflammatory response to early…

INTRODUCTION: Knowledge about the feasibility and effects of exercise programs to persons with Alzheimer's disease is lacking. This study investigated the effect of aerobic exercise on physical performance in community-dwelling persons with mild Alzheimer's disease. METHODS: The single blinded multi-center RCT (ADEX) included 200 patients, median age 71 yrs (50-89). The intervention group received supervised moderate-to-high intensity aerobic exercise 1 hour × 3/week for 16 weeks. Assessments included cardiorespiratory fitness, single-task physical performance, dual-task performance and exercise self-efficacy. RESULTS: Significant between-group differences in change from baseline (mean [95%CI]) favored the intervention group for cardiorespiratory fitness (4.0 [2.3-5.8] ml/kg/min, P <0.0001) and exercise self-efficacy (1.7 [0.5-2.8] points, P =0.004). Furthermore, an exercise attendance of ≥66.6% resulted in significant positive effects on single-task physical performance and dual-task performance. DISCUSSION: Aerobic exercise has the potential to improve cardiorespiratory fitness,…

A group of neurodegenerative diseases referred to as tauopathies are characterized by the presence of brain cells harboring inclusions of pathological species of the tau protein. These disorders include Alzheimer's disease and frontotemporal lobar degeneration due to tau pathology, including progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. Tau is normally a microtubule (MT)-associated protein that appears to play an important role in ensuring proper axonal transport, but in tauopathies tau becomes hyperphosphorylated and disengages from MTs, with consequent misfolding and deposition into inclusions that mainly affect neurons but also glia. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, and there is a growing interest in developing tau-directed therapeutic agents. The following review provides a summary of strategies under investigation for the potential treatment of tauopathies, highlighting both the promises and challenges associated with these various therapeutic…

O-GlcNAcylation is the posttranslational modification of intracellular proteins by O-linked β-N-acetylglucosamine (O-GlcNAc). The discovery of O-GlcNAc modification of tau and its impact on tau phosphorylation has attracted recent research interest in O-GlcNAc studies in the Alzheimer's disease (AD) field. Modification of proteins by O-GlcNAc occurs extensively in the brain. The expressions and activities of the enzymes catalyzing O-GlcNAc cycling are several-fold higher in the brain than in the peripheral tissues. The O-GlcNAcylation levels of brain proteins including tau are decreased in AD brain, probably due to decreased brain glucose metabolism. The reduction of brain O-GlcNAcylation appears to mediate the molecular mechanism by which decreased brain glucose metabolism contributes to neurodegeneration. Studies on mouse models of tauopathies suggest a neuroprotective role of pharmacological elevation of brain O-GlcNAc, which could potentially be a promising approach for treating AD and other neurodegenerative diseases.

Abstract Introduction Brain structural changes in preclinical Alzheimer's disease (AD) are poorly understood. Methods We compared the changes in cortical thickness in the ADNI cohort during a 2‐year follow‐up between the NIA‐AA preclinical AD stages defined by cerebrospinal fluid (CSF) biomarker levels. We also analyzed the correlation between baseline CSF biomarkers and cortical atrophy rates. Results At follow‐up, stage 1 subjects showed reduced atrophy rates in medial frontal areas and precuneus compared to stage 0 subjects, whereas stage 2/3 subjects presented accelerated atrophy in medial temporal structures. Low CSF Aβ 1–42 levels were associated with reduced atrophy rates in subjects with normal tau levels and high CSF tau levels with accelerated atrophy only in subjects with low Aβ 1–42 levels. Discussion Our longitudinal data confirm a biphasic trajectory of changes in brain structure in preclinical AD. These have implications in AD trials, both in patient selection and the use of MRI as a surrogate marker of efficacy.

INTRODUCTION: Epidemiologic studies have demonstrated an association between diabetes and dementia. Insulin signaling within the brain, in particular within the hypothalamus regulates carbohydrate, lipid, and branched chain amino acid (BCAA) metabolism in peripheral organs such as the liver and adipose tissue. We hypothesized that cerebral amyloidosis impairs central nervous system control of metabolism through disruption of insulin signaling in the hypothalamus, which dysregulates glucose and BCAA homeostasis resulting in increased susceptibility to diabetes. METHODS: We examined whether APP/PS1 mice exhibit increased susceptibility to aging or high-fat diet (HFD)-induced metabolic impairment using metabolic phenotyping and insulin-signaling studies. RESULTS: APP/PS1 mice were more susceptible to high-fat feeding and aging-induced metabolic dysregulation including disrupted BCAA homeostasis and exhibited impaired hypothalamic insulin signaling. DISCUSSION: Our data suggest that AD pathology increases susceptibility to diabetes due to impaired hypothalamic insulin signaling, and…

The Horizon 2020/IMI European Prevention of Alzheimer's Dementia (EPAD) project will undertake large-scale proof-of-concept trials in predementia Alzheimer's disease (AD). Within EPAD, the monitoring of cognitive trajectories in the preclinical period will constitute a central outcome measure; however, there are currently no clear guidelines as to how this should be achieved as most measures have been developed for the period around dementia diagnosis. The EPAD Scientific Advisory Group for Clinical and Cognitive Outcomes identified appropriate cognitive measures based on a literature search covering both cognitive correlates of preclinical brain changes from imaging studies and cognitive changes observed over time in nondementia population cohorts developing incident dementia. These measures were evaluated according to the following criteria: validity, coherence with biomarker changes, psychometric properties, cross-cultural suitability, availability of alternative forms, and normative data limited practice effects. The resulting consensus statement provides recommendations for…

INTRODUCTION: Recent literature proposes that amyloid β (Aβ) and phosphorylated tau (p-tau) synergism accelerates biomarker abnormalities in controls. Yet, it remains to be answered whether this synergism is the driving force behind Alzheimer disease (AD) dementia. METHODS: F]florbetapir positron emission tomography Aβ imaging and cerebrospinal fluid p-tau. Regression and voxel-based logistic regression models with interaction terms evaluated 2-year changes in cognition and clinical status as a function of baseline biomarkers. RESULTS: F]florbetapir and p-tau, rather than their additive effects, was associated with the cognitive decline and progression to AD. Furthermore, voxel-based analysis revealed that temporal and inferior parietal were the regions where the synergism determined an increased likelihood of developing AD. DISCUSSION: Together, the present results support that progression to AD dementia is driven by the synergistic rather than a mere additive effect between Aβ and p-tau proteins.

Recent findings have elucidated roles for mitochondrial uncoupling proteins (UCPs) in neuronal plasticity and resistance to metabolic and oxidative stress. UCPs are induced by bioenergetic challenges such as caloric restriction and exercise and may protect neurons against dysfunction and degeneration. The pharmacological uncoupler 2,4-dinitrophenol (DNP), which was once prescribed to >100,000 people as a treatment for obesity, stimulates several adaptive cellular stress-response signaling pathways in neurons including those involving the brain-derived neurotrophic factor (BDNF), the transcription factor cyclic AMP response element-binding protein (CREB), and autophagy. Preclinical data show that low doses of DNP can protect neurons and improve functional outcome in animal models of Alzheimer's and Parkinson's diseases, epilepsy, and cerebral ischemic stroke. Repurposing of DNP and the development of novel uncoupling agents with hormetic mechanisms of action provide opportunities for new breakthrough therapeutic interventions in a range of acute and chronic insidious…

Dementia is a global problem and major target for health care providers. Although up to 45% of cases are primarily or partly due to cerebrovascular disease, little is known of these mechanisms or treatments because most dementia research still focuses on pure Alzheimer's disease. An improved understanding of the vascular contributions to neurodegeneration and dementia, particularly by small vessel disease, is hampered by imprecise data, including the incidence and prevalence of symptomatic and clinically "silent" cerebrovascular disease, long-term outcomes (cognitive, stroke, or functional), and risk factors. New large collaborative studies with long follow-up are expensive and time consuming, yet substantial data to advance the field are available. In an initiative funded by the Joint Programme for Neurodegenerative Disease Research, 55 international experts surveyed and assessed available data, starting with European cohorts, to promote data sharing to advance understanding of how vascular disease affects brain structure and function, optimize methods for cerebrovascular disease…

INTRODUCTION: In Alzheimer's disease (AD), pathologic amyloid-beta (Aβ) is synaptotoxic and impairs neuronal function at the microscale, influencing brain networks at the macroscale before Aβ deposition. The latter can be detected noninvasively, in vivo, using resting-state functional MRI (rsfMRI), a technique used to assess brain functional connectivity (FC). METHODS: RsfMRI was performed longitudinally in TG2576 and PDAPP mice, starting before Aβ deposition to determine the earliest FC changes. Additionally, the role of pathologic Aβ on early FC alterations was investigated by treating TG2576 mice with the 3D6 anti-Aβ-antibody. RESULTS: Both transgenic models showed hypersynchronized FC before Aβ deposition and hyposynchronized FC at later stages. Early anti-Aβ treatment in TG2576 mice prevented hypersynchronous FC and the associated synaptic impairments and excitatory/inhibitory disbalances. DISCUSSION: Hypersynchrony of FC may be used as a new noninvasive read out of early AD and can be recovered by anti-Aβ treatment, encouraging preventive treatment strategies in familial AD.

INTRODUCTION: Compared to Caucasians, African Americans (AAs) have higher dementia prevalence, different genetic markers, and higher vascular risk factors. However, pathologic underpinnings are unknown. METHODS: We used neuropathologic and clinical data on 110 AA and 2500 Caucasians who were demented before death. The groups were compared regarding demographics, cognition, apolipoprotein E (APOE) genotype, comorbidities, and clinical and neuropathologic characteristics. RESULTS: AA and Caucasians differed in their demographics, cognition at the last visit before death, APOE genotype, presence of hypertension, primary clinical diagnoses, and AD, cerebrovascular disease (CVD), and other neuropathologies such as Lewy body disease (LBD). DISCUSSION: AD, LBD, and CVD pathology were more common and TDP and frontotemporal lobar degeneration-tau less common in AA than in Caucasians. APOE accounted for most of the AD neuropathologic differences. If replicated, the observed differences in underlying neuropathology by race will be important for public health policy and recruitment for and…

INTRODUCTION: Given that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need. METHODS: We investigated the plasma levels of Aβ, proNGF, tPA, neuroserpin, metallo-proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline. RESULTS: Aβ40 and Aβ42 were elevated in DS plasma compared to controls, even in DS individuals without dementia. Plasma Aβ correlated with the rate of cognitive decline across 2 years. ProNGF, MMP-1, MMP-3, MMP-9 activity, TNF-α, IL-6, and IL-10 were higher in DS plasma, even at AD-asymptomatic stages. Declining plasma Aβ42 and increasing proNGF levels correlated with cognitive decline. A combined measure of Aβ and inflammatory molecules was a strong predictor of prospective cognitive deterioration. CONCLUSIONS: Our findings support the combination of plasma and cognitive assessments for the identification of DS individuals at risk of dementia.

INTRODUCTION: Investigation of the conversion rates from normal cognition (NC) to mild cognitive impairment (MCI) is important, as effective early intervention could potentially prevent or substantially delay the onset of dementia. However, reported conversion rates differ across studies and recruitment source. Our study examined predictors of conversion from NC to MCI in a racially and ethnically diverse sample drawn both from community and clinic recruitment sources. METHODS: Rates and predictors of conversion were assessed in an ongoing prospective longitudinal study at University of California, Davis, Alzheimer's Disease Center from 2000 to 2015. Participants (n = 254) were recruited through a clinic (5%) and community sample (95%). They were clinically confirmed as cognitively normal at baseline and followed up to seven years. Recruitment source, demographic factors (age, gender, race/ethnicity, year of education, APOE ε4 positive), cognitive measures (SENAS test scores), functional assessments (CDR sum of boxes), and neuroimaging measures (total brain volume, total hippocampal…

INTRODUCTION: Cerebral small vessel disease (CSVD) is a highly prevalent condition associated with diffuse ischemic damage and cognitive dysfunction particularly in executive function and attention. Functional brain imaging studies can reveal mechanisms of cognitive impairment in CSVD, although findings are mixed. METHODS: A systematic review integrating findings from functional magnetic resonance imaging and electroencephalography in CSVD is involved. RESULTS: CSVD damages long-range white matter tracts connecting nodes within distributed brain networks. It also disrupts frontosubcortical circuits and cholinergic fiber tracts mediating attentional processes. These changes, illustrated within a model of network dynamics, synergistically relate to neurodegenerative pathology contributing to dementia. DISCUSSION: The effects of CSVD on attention and executive functioning are best understood within a network model of cognition as revealed by functional neuroimaging. Analysis of network function in CSVD can improve characterization of disease severity and treatment effects, and it can…

INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS: ), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.

NFT pathology emerges in the transentorhinal are and proceeds in a complex pattern through different medial temporal lobe (MTL) subregions and hippocampal subfields, eventually spreading to most of the cortex. Since neurodegeneration in AD closely follows NFT pathology, granular MRI-based measures of change in MTL subregions can be more sensitive biomarkers for treatment evaluation than conventional markers such as hippocampal volume, particularly in preclinical disease, when effects are subtle and largely contained to the MTL. Several large studies, including ADNI, collect T2-weighted MRI scans of the MTL that offer higher resolution and significantly better contrast for visualizing hippocampal and MTL subregion boundaries than conventional 1mm isotropic T1w MRI. We previously developed an automatic multi-atlas segmentation technique “ASHS” that extracts MTL subregion volume and thickness measures in 3T and 7T MRI scans, and showed that it is can reliably reproduce manual segmentation. Until now, however, ASHS required access to a high-performance computing cluster. Through…

Identifying accurate biomarkers of cognitive decline is essential for advancing early diagnosis and prevention therapies in Alzheimer's disease. The Alzheimer's disease DREAM Challenge was designed as a computational crowdsourced project to benchmark the current state-of-the-art in predicting cognitive outcomes in Alzheimer's disease based on high dimensional, publicly available genetic and structural imaging data. This meta-analysis failed to identify a meaningful predictor developed from either data modality, suggesting that alternate approaches should be considered for prediction of cognitive performance.

INTRODUCTION: Patients surviving stroke without immediate dementia are at high risk of delayed-onset dementia. Mechanisms underlying delayed-onset dementia are complex and may involve vascular and/or neurodegenerative diseases. METHODS: Dementia-free patients with stroke and/or transient ischemic attack (TIA; n = 919) were studied for 3 years prospectively, excluding those who developed dementia 3 to 6 months after stroke and/or TIA. RESULTS: Forty subjects (4.4%) developed dementia during the study period. Imaging markers of severe small vessel disease (SVD), namely presence of ≥3 lacunes and confluent white matter changes; history of hypertension and diabetes mellitus independently predicted delayed-onset dementia after adjustment for age, gender, and education. Only 6 of 31 (19.4%) subjects with delayed cognitive decline harbored Alzheimer's disease-like Pittsburg compound B (PiB) retention. Most PiB cases (16/25, 64%) had evidence of severe SVD. DISCUSSION: Severe SVD contributes importantly to delayed-onset dementia after stroke and/or TIA. Future clinical trials aiming to…

INTRODUCTION: The impact of blood pressure on brain volumes may be time-dependent or pattern-dependent. METHODS: Of 1678 participants from the Atherosclerosis Risk in Communities Neurocognitive Study, we quantified the association between measures and patterns of blood pressure over three time points (∼24 or ∼15 years prior and concurrent with neuroimaging) with late life brain volumes. RESULTS: Higher diastolic blood pressure ∼24 years prior, higher systolic and pulse pressure ∼15 years prior, and consistently elevated or rising systolic blood pressure from ∼15 years prior to concurrent with neuroimaging, but not blood pressures measured concurrent with neuroimaging, were associated with smaller volumes. The pattern of hypertension ∼15 years prior and hypotension concurrent with neuroimaging was associated with smaller volumes in regions preferentially affected by Alzheimer's disease (e.g., hippocampus: -0.27 standard units, 95% CI: -0.51, -0.03). DISCUSSION: Hypertension 15 to 24 years prior is relevant to current brain volumes. Hypertension followed by hypotension appears…

A major obstacle to presymptomatic diagnosis and disease-modifying therapy for Alzheimer's disease (AD) is inadequate understanding of molecular mechanisms of AD pathogenesis. For example, impaired brain insulin signaling is an AD hallmark, but whether and how it might contribute to the synaptic dysfunction and neuron death that underlie memory and cognitive impairment has been mysterious. Neuron death in AD is often caused by cell cycle reentry (CCR) mediated by amyloid-β oligomers (AβOs) and tau, the precursors of plaques and tangles. We now report that CCR results from AβO-induced activation of the protein kinase complex, mTORC1, at the plasma membrane and mTORC1-dependent tau phosphorylation, and that CCR can be prevented by insulin-stimulated activation of lysosomal mTORC1. AβOs were also shown previously to reduce neuronal insulin signaling. Our data therefore indicate that the decreased insulin signaling provoked by AβOs unleashes their toxic potential to cause neuronal CCR, and by extension, neuron death.

Massive investment and technological advances in the collection of extensive and longitudinal information on thousands of Alzheimer patients results in large amounts of data. These "big-data" databases can potentially advance CNS research and drug development. However, although necessary, they are not sufficient, and we posit that they must be matched with analytical methods that go beyond retrospective data-driven associations with various clinical phenotypes. Although these empirically derived associations can generate novel and useful hypotheses, they need to be organically integrated in a quantitative understanding of the pathology that can be actionable for drug discovery and development. We argue that mechanism-based modeling and simulation approaches, where existing domain knowledge is formally integrated using complexity science and quantitative systems pharmacology can be combined with data-driven analytics to generate predictive actionable knowledge for drug discovery programs, target validation, and optimization of clinical development.

INTRODUCTION: The present study investigated the relationship between beta-amyloid (Aβ) and cognition in a late middle-aged cohort at risk for Alzheimer's disease (AD). METHODS: One eighty-four participants (mean age = 60; 72% parental history of AD) completed a [C-11]Pittsburgh compound B positron emission tomography scan and serial cognitive evaluations. A global measure of Aβ burden was calculated, and composite scores assessing learning, delayed memory, and executive functioning were computed. RESULTS: Higher Aβ was associated with classification of psychometric mild cognitive impairment (MCI) at follow-up (P < .01). Linear mixed effects regression results indicated higher Aβ was associated with greater rates of decline in delayed memory (P < .01) and executive functioning (P < .05). Apolipoprotein E (APOE) ε4 status moderated the relationship between Aβ and cognitive trajectories (P values <.01). DISCUSSION: In individuals at risk for AD, greater Aβ in late middle age is associated with increased likelihood of MCI at follow-up and steeper rates of cognitive decline.

INTRODUCTION: White matter hyperintensities (WMHs) increase the risk of Alzheimer's disease (AD). Whether WMHs are associated with the decline of functional neural networks in AD is debated. METHOD: Resting-state functional magnetic resonance imaging and WMH were assessed in 78 subjects with increased amyloid levels on AV-45 positron emission tomography (PET) in different clinical stages of AD. We tested the association between WMH volume in major atlas-based fiber tract regions of interest (ROIs) and changes in functional connectivity (FC) between the tracts' projection areas within the default mode network (DMN). RESULTS: WMH volume within the inferior fronto-occipital fasciculus (IFOF) was the highest among all tract ROIs and associated with reduced FC in IFOF-connected DMN areas, independently of global AV-45 PET. Higher AV-45 PET contributed to reduced FC in IFOF-connected, temporal, and parietal DMN areas. CONCLUSIONS: High fiber tract WMH burden is associated with reduced FC in connected areas, thus adding to the effects of amyloid pathology on neuronal network function.

The methodology of Genome-Wide Association Screening (GWAS) has been applied for more than a decade. Translation to clinical utility has been limited, especially in Alzheimer's Disease (AD). It has become standard practice in the analyses of more than two dozen AD GWAS studies to exclude the apolipoprotein E (APOE) region because of its extraordinary statistical support, unique thus far in complex human diseases. New genes associated with AD are proposed frequently based on SNPs associated with odds ratio (OR) < 1.2. Most of these SNPs are not located within the associated gene exons or introns but are located variable distances away. Often pathologic hypotheses for these genes are presented, with little or no experimental support. By eliminating the analyses of the APOE-TOMM40 linkage disequilibrium region, the relationship and data of several genes that are co-located in that LD region have been largely ignored. Early negative interpretations limited the interest of understanding the genetic data derived from GWAS, particularly regarding the TOMM40 gene. This commentary describes…

INTRODUCTION: We estimated the prevalence of microinfarcts and their association with dementia in a cohort of oldest-old participants. METHODS: Participants were from The 90+ Study, a population-based study of people 90 years and older. Dementia diagnoses were assigned postmortem during a consensus conference. Microinfarcts were evaluated in six brain regions. RESULTS: At death, the 213 participants were on average 97 years old, 69% were women, and 52% had dementia. Of the participants, 51% had microinfarcts and 17% had 3+ microinfarcts. The odds ratio (OR) for dementia was similar for 3+ microinfarcts (OR = 4.75, P < .01) and tangle stage V-VI (OR = 4.70, P < .001). Only microinfarcts in cortical regions (other than occipital) were associated to dementia. DISCUSSION: In this oldest-old cohort, microinfarcts are common and contribute independently and similarly in magnitude to dementia as tangles. As risk factors for microinfarcts and other dementing pathologies are likely to differ, identifying these factors is crucial to developing prevention strategies for dementia in the…

INTRODUCTION: Molecular biomarkers for Alzheimer's disease (AD) can support detection and improved care for patients, but novel candidates require verification. We previously reported a 12-micro RNA (miRNA) blood-based signature using next-generation sequencing (NGS) of 54 AD cases and 22 controls. METHODS: We performed validation of 49 AD cases and 55 controls using NGS and also included 20 mild cognitive impairment and 90 multiple sclerosis samples to identify nonspecific markers. Thus, 103 AD cases, 77 unaffected controls, and 110 diseased controls were sequenced. Although the initial cohort came predominantly from the United States, the validation samples were collected in Germany. RESULTS: Five hundred eighty miRNAs were detected in the blood. In the initial cohort, we observed 203, in the validation cohort, 146 dysregulated miRNAs at a significance level of 0.05. With 68 miRNAs, the overlap was significant (P = .0003). Likewise, the area under the receiver operator characteristic curve values of the miRNAs correlated (correlation of 0.93; 95% confidence interval 0.89-0.96; P…

INTRODUCTION: Individuals with amnestic mild cognitive impairment (aMCI) are at elevated risk of developing Alzheimer's disease (AD) dementia. METHODS: With data from the Aging, Demographics, and Memory Study, we used the Clinical Dementia Rating Sum of Boxes classifications to conduct a cross-sectional analysis assessing the relationship between cognitive state and various direct and indirect costs and health care utilization patterns. RESULTS: Patients with aMCI had less medical expenditures than patients with moderate and severe AD dementia (P < .001) and were also significantly less likely to have been hospitalized (P = .04) and admitted to nursing home (P < .001). Compared to individuals with normal cognition, patients with aMCI had significantly less household income (P = .018). DISCUSSION: Patients with aMCI had lower medical expenditures than patients with AD dementia. Poor cognitive status was linearly associated with lower household income, higher medical expenditures, higher likelihood of nursing and home care services, and lower likelihood of outpatient visits.

A pathological pathway leading from soluble to insoluble and filamentous tau underlies human tauopathies. This ordered assembly causes disease and is the gain-of-toxic function. It involves the transition from an intrinsically disordered monomer to a highly structured filament. Based on recent findings, one can divide the ordered assembly into propagation of pathology and neurodegeneration. Short tau fibrils constitute the major species of seed-competent tau in the brains of mice transgenic for human P301S tau. The molecular species of aggregated tau that are essential for neurodegeneration remain to be identified.

INTRODUCTION: The underlying pathological mechanisms linking cardiovascular burden to cognitive decline remain unclear. METHODS: We investigated the associations of the Framingham general cardiovascular risk score (FGCRS), apolipoprotein E (APOE) ε4, and brain structure with the Mini-Mental State Examination (MMSE) decline using the 9-year follow-up data from Swedish National Study on Aging and Care in Kungsholmen (n = 2189, age ≥60) and the embedded magnetic resonance imaging (MRI) (n = 448) studies. Volumes of white matter hyperintensities (WMHs), total gray matter, ventricles, and hippocampus were assessed in the MRI sample. RESULTS: A higher FGCRS was associated with faster MMSE decline in young-old people (60-72 years) but not in old-old (≥78 years). Larger volumes of cerebral WMHs and ventricles and smaller volumes of total gray matter and hippocampus were all associated with accelerated MMSE decline (P < .01); these associations were stronger among APOE ε4 carriers than noncarriers. Simultaneously entering multiple brain lesion markers as mediators in the model substantially…

Alzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants.

Abstract Introduction We hypothesized that common Alzheimer's disease (AD)‐associated variants within the triggering receptor expressed on myeloid (TREM) gene cluster influence disease through gene expression. Methods Expression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis. Results A variant within a DNase hypersensitive site 5′ of TREM2, rs9357347‐C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10−3 and 4.6 × 10−2, respectively). Meta‐analysis on expression quantitative trait locus results from three independent data sets (n = 1006) confirmed these associations (uncorrected P = 3.4 × 10−2 and 3.5 × 10−3, Bonferroni‐corrected P = 6.7 × 10−2 and 7.1 × 10−3, respectively). Discussion Our findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome‐wide…

INTRODUCTION: Cerebrovascular lesions on MRI are common in Alzheimer's disease (AD) dementia, but less is known about their frequency and impact on dementia with Lewy bodies (DLB). METHODS: White-matter hyperintensities (WMHs) and infarcts on MRI were assessed in consecutive DLB (n = 81) and AD dementia (n = 240) patients and compared to age-matched and sex-matched cognitively normal subjects (CN) from a population-based cohort. RESULTS: DLB had higher WMH volume compared to CN, and WMH volume was higher in the occipital and posterior periventricular regions in DLB compared to AD. Higher WMH volume was associated with history of cardiovascular disease and diabetes but not with clinical disease severity in DLB. Frequency of infarcts in DLB was not different from CN and AD dementia. DISCUSSION: In DLB, WMH volume is higher than AD and CN and appears to be primarily associated with history of vascular disease.

INTRODUCTION: Accurate diagnosis of prion diseases and discrimination from alternative dementias gain importance in the clinical routine, but partial overlap in cerebrospinal fluid (CSF) biomarkers impedes absolute discrimination in the differential diagnostic context. METHODS: We established the clinical parameters for prion disease diagnosis for the quantification of CSF α-synuclein in patients with sporadic (n = 234) and genetic (n = 56) prion diseases, in cases with cognitive impairment/dementia or neurodegenerative disease (n = 278), and in the neurologic control group (n = 111). RESULTS: An optimal cutoff value of 680 pg/mL α-synuclein results in 94% sensitivity and 96% specificity when diagnosing sporadic Creutzfeldt-Jakob disease (CJD). Genetic CJD cases showed increased CSF α-synuclein values. No increased α-synuclein levels were detected in non-CJD cases with rapid progression course. DISCUSSION: Detection of α-synuclein in the CSF of patients with suspected CJD is a valuable diagnostic test reaching almost full discrimination from non-prion disease cases. These data…

INTRODUCTION: Subjective cognitive decline (SCD) is a risk factor for mild cognitive impairment (MCI) and Alzheimer's disease (AD). Although sleep has been shown to be altered in MCI and AD, little is known about sleep in SCD. METHODS: Seventy cognitively normal community-dwelling participants were classified as SCD (32) or controls (38) using the Subjective Cognitive Decline Questionnaire. Sleep was assessed using actigraphy and diaries. FreeSurfer was used for performing medial temporal lobes (MTLs) and brain cortical parcellation of 3T magnetic resonance images. Multiple regression models were used to assess the presence of sleep, MTL, or regional cortical differences between groups. RESULTS: Objective sleep was disrupted in SCD participants, which showed increased nighttime wakefulness and reduced sleep efficiency. No group differences emerged in subjective sleep or magnetic resonance imaging outcomes. DISCUSSION: Objective sleep resulted disrupted in community-dwelling SCD, without any subjective sleep or cortical change. Sleep assessment/intervention in SCD might help…

INTRODUCTION: Under the U.S. national Alzheimer's plan, the National Institutes of Health identified milestones required to meet the plan's biomedical research goal (Goal 1). However, similar milestones have not been created for the goals on care (Goal 2) and support (Goal 3). METHODS: The Alzheimer's Association convened a workgroup with expertise in clinical care, long-term services and supports, dementia care and support research, and public policy. The workgroup reviewed the literature on Alzheimer's care and support; reviewed how other countries are addressing the issue; and identified public policies needed over the next 10 years to achieve a more ideal care and support system. RESULTS: The workgroup developed and recommended 73 milestones for Goal 2 and 56 milestones for Goal 3. DISCUSSION: To advance the implementation of the U.S. national Alzheimer's plan, the U.S. government should adopt these recommended milestones, or develop similar milestones, to be incorporated into the national plan.

INTRODUCTION: Accumulation of hyperphosphorylated tau and the disruption of microtubules are correlated with synaptic loss and pathology of Alzheimer's disease (AD). Impaired cognitive function and pathology of AD is correlated with this lesion. This review looks at the mechanism of neurodegeneration, the prion-like behavior of tau in its interaction with normal MAPs in correlation with tau hyperphosphorylation. METHODS: We reviewed our work in the field as well as current literature that pertains to tau phosphorylation and the biological effects. RESULTS: Hyperphosphorylation of tau in AD, in vitro, in cells, or in animal models converts this protein into a prion-like protein that is able to propagate the altered conformation. DISCUSSION: These findings suggest that phosphorylation of tau is a critical event in neurodegeneration. The combination of phosphorylation sites can generate a gain of toxic function for tau. The mechanism of tau toxicity might involve not only the microtubule system but also interference with other cellular compartments such as the nucleus and the actin…

INTRODUCTION: We develop a multidomain model to predict progression of Alzheimer's disease dementia (AD). METHODS: Data from the US National Alzheimer's Coordinating Center (n = 3009) are used to examine change in symptom status and to estimate transition probabilities between health states described using cognitive function, functional ability, and behavior. A model is used to predict progression and to assess a hypothetical treatment scenario that slows mild to moderate AD progression. RESULTS: More than 70% of participants moved state over 12 months. The majority moved in domains other than cognitive function. Over 5 years, of those alive more than half are in severe AD health states. Assessing an intervention scenario, we see fewer years in more severe health states and a potential impact (life years saved) due to mortality improvements. DISCUSSION: The model developed is exploratory and has limitations but illustrates the importance of using a multidomain approach when assessing impacts of AD and interventions.

INTRODUCTION: We investigated the change in DNA methylation in peripheral blood CD4+ lymphocytes over time, examined the relation between CD4+ lymphocytes and brain methylation, and compared their associations with AD pathology. METHODS: Genome-wide methylation was measured three times in 41 older persons using Illumina Infinium HumanMethylation450 array. The two CD4+ lymphocytes measures were at study baseline and proximate to death. Brain tissue came from frozen dorsolateral prefrontal cortex. RESULTS: Global methylation features were conserved across tissue. At individual CpG sites, methylation level was concordant between the two CD4+ lymphocytes but more diffuse between CD4+ lymphocytes and brain. Previous associations of brain methylation with neuritic plaques at target methylation sites were not replicated in CD4+ lymphocytes. DISCUSSION: There is no strong evidence of change in CD4+ lymphocytes methylation among older persons over an average of 7.5 years. Methylation associations with AD pathology found in neocortex are not directly reflected in CD4+ lymphocytes.

INTRODUCTION: Memory loss and increased anxiety are clinical hallmarks of Alzheimer's disease (AD). Kallikrein-8 is a protease implicated in memory acquisition and anxiety, and its mRNA is known to be up-regulated in AD-affected human hippocampus. Therefore, an involvement of Kallikrein-8 in Alzheimer's pathogenesis is conceivable but remains to be proved. METHODS: We determined the cerebral expression of Kallikrein-8 mRNA and protein during the course of AD in patients and in transgenic mice and tested the impact of Kallikrein-8 inhibition on AD-related pathology in mice and in primary glial cells. RESULTS: Kallikrein-8 mRNA and protein were up-regulated in both species at incipient stages of AD. Kallikrein-8 inhibition impeded amyloidogenic amyloid-precursor-protein processing, facilitated amyloid β (Aβ) clearance across the blood-brain-barrier, boosted autophagy, reduced Aβ load and tau pathology, enhanced neuroplasticity, reversed molecular signatures of anxiety, and ultimately improved memory and reduced fear. DISCUSSION: Kallikrein-8 is a promising new therapeutic target…

INTRODUCTION: "Walkable" neighborhoods offer older adults opportunities for activities that may benefit cognition-related biological mechanisms. These have not previously been examined in this context. METHODS: We objectively assessed neighborhood walkability for participants (n = 146) from the Australian Imaging, Biomarkers and Lifestyle study with apolipoprotein E (APOE) genotype and two 18-month-apart brain volumetric and/or amyloid β burden assessments. Linear mixed models estimated associations of neighborhood walkability with levels and changes in brain imaging outcomes, the moderating effect of APOE ε4 status, and the extent to which associations were explained by physical activity. RESULTS: Cross-sectionally, neighborhood walkability was predictive of better neuroimaging outcomes except for left hippocampal volume. These associations were to a small extent explained by physical activity. APOE ε4 carriers showed slower worsening of outcomes if living in walkable neighborhoods. DISCUSSION: These findings indicate associations between neighborhood walkability and brain imaging…

INTRODUCTION: We assessed the association of gamma glutamyltransferase (GGT) with risk of dementia. METHODS: Serum GGT activity was assessed at baseline in the Kuopio Ischemic Heart Disease prospective cohort of 2415 relatively healthy men with good cognitive function. Correction was made for within-person variability in GGT levels. RESULTS: During an average follow-up of 22 years, 219 new cases of dementia were recorded. Serum GGT was log-linearly associated with risk of dementia. The hazard ratio (HR) (95% CIs) for dementia per 1 standard deviation (SD) higher baseline loge GGT values was 1.33 (95% CI = 1.14-1.55) after adjustment for several established and emerging risk factors. The corresponding HR was 1.52 (95% CI = 1.22-1.89) after correction for within-person variability. DISCUSSION: GGT is positively, log-linearly, and independently associated with future risk of dementia in the general male population. Further research is needed to unravel the mechanistic pathways of GGT in the pathogenesis of dementia.

INTRODUCTION: The MAPT H1 haplotype has been associated with several neurodegenerative diseases. We were interested in exploring the role of MAPT haplotypic variation in risk of dementia with Lewy bodies (DLB). METHOD: We genotyped six MAPT haplotype tagging SNPs and screened 431 clinical DLB cases, 347 pathologically defined high-likelihood DLB cases, and 1049 controls. RESULT: We performed haplotypic association tests and detected an association with the protective H2 haplotype in our combined series (odds ratio [OR] = 0.75). We fine-mapped the locus and identified a relatively rare haplotype, H1G, that is associated with an increased risk of DLB (OR = 3.30, P = .0017). This association was replicated in our pathologically defined series (OR = 2.26, P = .035). DISCUSSION: These results support a role for H1 and specifically H1G in susceptibility to DLB. However, the exact functional variant at the locus is still unknown, and additional studies are warranted to fully explain genetic risk of DLB at the MAPT locus.

INTRODUCTION: Previous studies have demonstrated that an overall high level of mental work demands decreased dementia risk. In our study, we investigated whether this effect is driven by specific mental work demands and whether it is exposure dependent. METHODS: Patients aged 75+ years were recruited from general practitioners and participated in up to seven assessment waves (every 1.5 years) of the longitudinal AgeCoDe study. Analyses of the impact of specific mental work demands on dementia risk were carried out via multivariate regression modeling (n = 2315). RESULTS: We observed a significantly lower dementia risk in individuals with a higher level of "information processing" (HR, 0.888), "pattern detection" (HR, 0.878), "mathematics" (HR, 0.878), and "creativity" (HR, 0.878). Yet, exposure-dependent effects were only significant for "information processing" and "pattern detection." DISCUSSION: Our longitudinal observations suggest that dementia risk may be reduced by some but not all types of mental work demands.

Given the complex neuropathology Alzheimer's disease (AD), combination therapy may be necessary for effective treatment. However, scientific, pragmatic, regulatory, and business challenges need to be addressed before combination therapy for AD can become a reality. Leaders from academia and industry, along with a former member of the Food and Drug Administration and the Alzheimer's Association, have explored these challenges and here propose a strategy to facilitate proof-of-concept combination therapy trials in the near future. First, a more integrated understanding of the complex pathophysiology and progression of AD is needed to identify the appropriate pathways and the disease stage to target. Once drug candidates are identified, novel clinical trial designs and selection of appropriate outcome assessments will be needed to enable definition and evaluation of the appropriate dose and dosing regimen and determination of efficacy. Success in addressing this urgent problem will only be achieved through collaboration among multiple stakeholders.

INTRODUCTION: Pathogenesis of Alzheimer's disease (AD) in apolipoprotein E ε4 (APOE ε4) carriers remains unclear. We hypothesize that APOE isoforms have differential effects on synaptic function. METHODS: We compared levels of CSF neurogranin (Ng) between APOE ε4 carriers and noncarriers in 399 subjects with normal cognition, mild cognitive impairment (MCI), and AD. We examined associations between Ng levels and age, education, gender, CSF-Aβ42, and tau protein. RESULTS: Neurogranin levels were significantly higher in APOE ε4 carriers compared to APOE ε4 noncarriers with MCI. Levels of Ng between the APOE ε4 carriers and APOE ε4 noncarriers with AD did not differ. Ng levels were correlated with MMSE and levels of tau and Aβ42. DISCUSSION: Significantly higher CSF Ng levels in APOE ε4 carriers with MCI may reflect synaptic injury underlying early cognitive impairment. Neurogranin may be an early biomarker of AD and important for disease diagnosis and timing of intervention in APOE ε4 carriers.

INTRODUCTION: The corticobasal syndrome (CBS) constitutes a neurodegenerative disease spectrum with substantial phenotypical or biological heterogeneity, requiring large or multimodal studies to identify its clinico-biological signature while disentangling Alzheimer's disease (AD)-related from non-AD-related CBS. METHODS: We analyzed a large (N = 45) monocenter expert-clinic CBS cohort, recruited in motor and/or cognitive units to avoid recruitment biases, assessed with standardized motor and/or cognitive-language tests, brain perfusion imaging, and cerebrospinal fluid biomarkers. RESULTS: CBS mainly manifests as a motor and/or language disorder incorporating a "mixed progressive aphasia" phenotype, consistent with left-lateralized damage to frontal-parietal-temporal cortices. Biomarker expression indicates in 18% underlying AD causing predominant parietal-temporal damage and Gerstmann syndrome (sensitivity 75%; specificity 75%), whereas non-AD-CBS presented with predominant prefrontal and lexical-semantic impairment. DISCUSSION: CBS is primarily a "motor-plus-aphasia" disease…

INTRODUCTION: The inhibition of the β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a main therapeutic approach for the treatment of Alzheimer's disease (AD). We previously reported an age-related increase of tau protein in the cerebrospinal fluid (CSF) of amyloid β (Aβ) precursor protein (APP) transgenic mice. METHODS: APP transgenic mice were treated with a potent BACE1 inhibitor. CSF tau and CSF Aβ levels were assessed. A novel high-sensitivity tau sandwich immunoassay was developed. RESULTS: We demonstrate that long-term BACE1 inhibition prevents CSF tau increase both in early-depositing APP transgenic mice and APP transgenic mice with moderate Aβ pathology. DISCUSSION: Our results demonstrate that BACE1 inhibition not only reduces Aβ generation but also downstream AD pathophysiology. The tight correlation between Aβ aggregation in brain and CSF tau levels renders CSF tau a valuable marker to predict the effectiveness of BACE1 inhibitors in current clinical trials.

INTRODUCTION: The number of persons aged >90 years will grow significantly in coming decades. This group has the highest rates of dementia, most commonly Alzheimer's disease (AD). METHODS: Using The 90+ Study, we developed a statistical model for dementia risk based on brain pathologies. Intervention scenarios which reduce or eliminate AD pathology were considered, and the numbers of dementia cases among the U.S. oldest-old that could be prevented were estimated. RESULTS: The U.S. dementia prevalence among the oldest-old will increase from 1.35 million in 2015 to 4.72 million in 2050. If interventions eliminate AD pathology, dementia prevalence would be reduced by approximately 50%, averting nearly 2.4 million cases in 2050. However, large numbers of dementia cases would still remain. DISCUSSION: Reducing AD pathology would significantly decrease the public health burden of dementia. However, other interventions are needed to address the burden associated with other dementing pathologies prevalent in the oldest-old.

INTRODUCTION: The presence of cerebrovascular pathology may increase the risk of clinical diagnosis of Alzheimer's disease (AD). METHODS: We examined excess risk of incident clinical diagnosis of AD (probable and possible AD) posed by the presence of lacunes and large infarcts beyond AD pathology using data from the Statistical Modeling of Aging and Risk of Transition study, a consortium of longitudinal cohort studies with more than 2000 autopsies. We created six mutually exclusive pathology patterns combining three levels of AD pathology (low, moderate, or high AD pathology) and two levels of vascular pathology (without lacunes and large infarcts or with lacunes and/or large infarcts). RESULTS: The coexistence of lacunes and large infarcts results in higher likelihood of clinical diagnosis of AD only when AD pathology burden is low. DISCUSSION: Our results reinforce the diagnostic importance of AD pathology in clinical AD. Further harmonization of assessment approaches for vascular pathologies is required.

Summary Work in the past 10 years has greatly expanded our understanding of Alzheimer's disease (AD) genetics, with more than 20 susceptibility genetic loci discovered in large genome‐wide association and sequencing studies. The NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is funded by National Institute on Aging to serve as a one‐stop portal for the community to access research data and findings generated from AD genetics projects. In this article, we describe the mission of NIAGADS, available resources, and data sets including the Alzheimer's Disease Sequencing Project, and how researchers may apply for access to genetic data.

INTRODUCTION: Identifying factors associated with lower dementia care costs is essential. We examined whether two caregiver factors were associated with lower costs of informal care. METHODS: A total of 271 care dyads of the Cache County Dementia Study were included. Estimates of informal costs were based on caregiver reports of time spent in care-related activities and inflation-adjusted 2012 Utah median hourly wages. Caregiver coping and emotional closeness with the care-recipient were assessed using the Ways of Coping Checklist-Revised and Relationship Closeness Scale, respectively. RESULTS: Higher closeness was associated with 24% lower costs (expβ = 0.763 [95% confidence interval: 0.583-0.999]) in linear mixed models controlling for demographics and baseline dementia severity and duration. Problem-focused coping was not associated with informal costs (P = .354). DISCUSSION: Caregiver closeness, a potentially modifiable factor, predicted lower dementia informal care costs over time. Future studies examining the care environment in closer dyads may identify specific care-related…